MiT/TFE family members suppress L-leucyl–L-leucine methyl ester-induced cell death

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  • Yabuki Ayaka
    Graduate School of Biomedical and Health Sciences, Hiroshima University
  • Miyara Masatsugu
    Graduate School of Biomedical and Health Sciences, Hiroshima University Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University Research Fellow of Japan Society for the Promotion of Science
  • Umeda-Miyara Kanae
    Graduate School of Biomedical and Health Sciences, Hiroshima University
  • Takao Saya
    Graduate School of Biomedical and Health Sciences, Hiroshima University
  • Sanoh Seigo
    Graduate School of Biomedical and Health Sciences, Hiroshima University
  • Kotake Yaichiro
    Graduate School of Biomedical and Health Sciences, Hiroshima University

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Abstract

<p>Lysosomes are degradative organelles essential for cell homeostasis. However, various internal and external stimuli, including L-leucyl–L-leucine methyl ester (LLOMe), which is one of the common lysosomotropic agents, permeabilize the lysosomal membrane, leading to lysosome-dependent cell death because of leakage of lysosomal contents to the cytosol. The microphthalmia/transcription factor E (MiT/TFE) family members, which include transcription factor EB (TFEB), transcription factor E3 (TFE3), and microphthalmia-associated transcription factor (MITF), are master regulators of lysosomal biogenesis and are known to be involved in the lysosomal stress response. However, their protective effects against cell death associated with lysosomal-membrane damage are still poorly understood. In this study, we confirmed that LLOMe-induced lysosomal damage triggered nuclear translocation of TFEB/TFE3/MITF and increased the mRNA levels of their target genes encoding lysosomal hydrolases and lysosomal membrane proteins in HeLa cells. Furthermore, we revealed that TFEB/TFE3/MITF knockdown exacerbated LLOMe-induced cell death. However, TFEB overexpression only slightly attenuated LLOMe-induced cell death, despite enhanced LLOMe-induced increase in CTSD mRNA levels, implying that the endogenous levels of MiT/TFE family members might be sufficient to promote lysosomal biogenesis in response to lysosomal-membrane damage. Our results suggest that MiT/TFE family members suppress the cell death associated with lysosomal-membrane damage.</p>

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